Fig. The changing dynamics of CpG depletion in SARS-CoV-2 genomes over time: a schematic representation

A team of IIT Delhi researchers have discovered the existence of temporal variations in selection pressures during SARS-CoV-2 evolution and adaptation to the human host. CpG (or CG; i.e. a cytosine followed by a guanine) numbers in virus genomes has been linked to host-switching, efficiency of virus replication, immune evasion and the ability of a virus to cause disease.

Zinc-finger antiviral protein (ZAP), a host protein that can bind to CpG-rich regions in SARS-CoV-2 (and other RNA viruses) and recruits other host proteins to degrade the viral RNA. Several viruses including HIV-1, Influenza A virus and SARS-CoV-2 prefer to reduce their CpG content (by losing CpGs) to minimize the host immune response, thus allowing better virus replication and survival.

The team analyzed over 1.4 million full-length SARS-CoV-2 sequences from across the world. They found that the rate of CpG depletion from SARS-CoV-2 genomes rapidly decreases after the first few months of evolution in humans. Furthermore, most SARS-CoV-2 variants of concern had lower CpG content. This work highlights the existence of selection pressures apart from ZAP that may lead to CpG depletion in SARS-CoV-2 genomes.

SARS-CoV-2 has a uracil-rich (uracil is one of the 4 building blocks of RNA) genome. We have identified how uracils adjacent to CpGs contribute to the accelerated loss of CpGs from SARS-CoV-2 genomes.

This work led by Prof. Vivekanandan Perumal from the Kusuma School of Biological Sciences, IIT Delhi has been published in the journal Molecular Biology and Evolution and is titled “The Slowing Rate of CpG Depletion in SARS-CoV-2 Genomes Is Consistent with Adaptations to the Human Host” (https://doi.org/10.1093/molbev/msac029).

Prof. Manoj Menon, a co-author of the publication, said, “Our results lay the necessary groundwork for future studies on understanding the intricacies of virus-host interactions leading to CpG depletion”.

Dr. Sonam Dhamija, another co-author on the paper, added, “This work has relevance to our current understanding of SARS-CoV-2 pathogenesis, immune evasion and emergence of variants of concern”.

The team includes Akhil Kumar, Nishank Goyal, Nandhini Saranathan and Saurabh Saraswat from IIT Delhi.

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